Pathogenesis of SIV in African green monkeys

项目描述（由申请人提供）：本项目旨在研究非洲绿猴（AGMs） SIVagm的发病机制。该物种能够应对高水平的SIVagm复制而不会产生负面后果。我们对年度股东大会如何做到这一点的理解有限。我们的初步结果描述了agm中SIV感染的悖论，其特征是：a)高血浆VLs，相当于致病性SIV感染；b)“经典”SIV靶细胞（定义为CD4+CCR5+CD45RAneg T细胞）的缺乏；c)慢性SIVagm感染中CD4+ T细胞的保存。因此，我们假设致病性和非致病性SIV感染在靶细胞、免疫细胞表型、组织病毒复制位点和体内病毒动力学方面存在定量差异，这可能解释了这种自然宿主对艾滋病的抗性。为了验证这一假设，我们提出了以下具体目的（SA）： SA1：比较源自加勒比的AGMs中SIVagm的发病机制与由SIVagm引起的艾滋病易感的异源宿主的发病机制；长尾猕猴据报道，这两个物种的SIVagm感染的临床结果不同，但研究仅限于血浆中的VLs。很少有关于sivagm感染的agm和ptm的免疫学数据。因此，我们的建议将集中在sivagm感染的AGMs和PTMs组织中的病毒和免疫学参数。我们将比较感染相同SIVagm菌株的两种宿主的病毒复制、细胞表型、增殖和凋亡位点。此外，SIVagm的主要靶细胞将在两个宿主中确定。目的：研究SIVagm在体内的病毒动力学，并确定SIVagm感染的AGMs和PTMs中短寿命细胞和长寿命细胞对总血浆病毒载量的相对贡献。SIVagm在其天然宿主中感染的悖论表明，致病性和非致病性模型在病毒爆发大小、病毒清除率或各种类型靶细胞的寿命方面存在潜在差异。我们将比较SIVagm在AGMs和PTMs中的体内动态和靶细胞，使用类似的方法用于SIVmac和HIV-1。

DESCRIPTION (provided by applicant): The objective of this project is to examine the pathogenesis of SIVagm in African green monkeys (AGMs). This species is able to cope with high levels of SIVagm replication without negative consequences. Our understanding of how AGMs are able to do this is limited. Our preliminary results depict a paradox of SIVagm infection in AGMs, characterized by: a) high plasma VLs, equivalent to pathogenic SIV infections; b) a paucity of "classical" SIV target cells (defined as CD4+CCR5+CD45RAneg T cells and; c) preservation of CD4+ T cells in chronic SIVagm infection. Therefore, we hypothesize that there are quantitative differences in target cells, immune cell phenotypes, sites of tissue viral replication and in vivo viral dynamics between pathogenic and non-pathogenic SIV infections which may explain the resistance to AIDS in this natural host. To examine this hypothesis, we propose the following Specific Aims (SA): SA1: To compare the pathogenesis of SIVagm in AGMs of Carribean origin to that of a heterologous host susceptible to AIDS caused by SIVagm; pig-tailed macaques (PTMs). A different clinical outcome of SIVagm infection was reported for these two species, but studies were limited to VLs in plasma. Few immunologic data is available for SIVagm-infected AGMs and PTMs. Therefore, our proposal will focus on viral and immunological parameters in tissues of SIVagm-infected AGMs and PTMs. We will compare these two hosts infected with the same SIVagm strain for sites of viral replication, cell phenotypes, proliferation and apoptosis. Also, the major target cells for SIVagm will be determined in both hosts. SA2: To examine SIVagm viral dynamics in vivo, and to determine the relative contribution of short and long-lived cells to the total plasma viral loads in SIVagm-infected AGMs and PTMs. The paradox of SIVagm infection in its natural host suggests potential differences between pathogenic and non-pathogenic models in viral burst size, viral clearance rates or the life span of various types of target cells. We will compare the in vivo dynamics and target cells of SIVagm in AGMs and PTMs, using similar approaches that have been used for SIVmac and HIV-1. Combined, these aims are designed to determine the viral and/or host factors responsible for resistance to AIDS.